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Background: Juvenile myelomonocytic leukemia (JMML) is a rare RAS/MAPK-driven pediatric myelodysplastic/myeloproliferative neoplasm. The phenotype and survival relevance of NRAS/KRAS alterations remain difficult to interpret because of co-mutations, evolving sequencing, incomplete germline confirmation, and post-diagnostic HSCT. Methods: We retrospectively reviewed 34 children with JMML and classifiable NRAS and/or KRAS alterations diagnosed between November 2010 and September 2022. Patients were classified as NRAS-only, KRAS-only, or NRAS/KRAS co-mutated. Direct comparisons used single-subtype cases. OS was analyzed in evaluable patients, with HSCT modeled as a time-dependent covariate. Results: The cohort included 20 NRAS-only, 12 KRAS-only, and 2 NRAS/KRAS co-mutated cases. KRAS-only cases had higher monocyte percentage (27.2% vs. 16.7%; p = 0.023) and lymphocyte percentage (48.1% vs. 39.0%; p = 0.018), whereas absolute monocyte count was comparable (4.0 vs. 4.0 × 109/L; p = 0.930). PTPN11 was the most frequent non-RAS co-mutation (7/34) and occurred in both NRAS/KRAS co-mutated cases. Methylation status was available in 11 patients and analyzed descriptively. NRAS/KRAS subtype did not significantly stratify OS (HR for KRAS-only vs. NRAS-only, 0.55; 95% CI, 0.18–1.62; p = 0.276). HbF did not significantly stratify OS, while diagnostic total hemoglobin showed only an exploratory univariable association. Exact HSCT dates were retrieved for all 11 transplanted patients; time-dependent Cox analysis showed a significant association between HSCT and better OS (HR, 0.11; 95% CI, 0.02–0.56; p = 0.007). Conclusions: NRAS/KRAS status defined a limited diagnosis-time phenotype but did not independently stratify survival. JMML survival analyses should integrate co-mutations, germline and testing-era limitations, HbF/hemoglobin risk context, and time-dependent HSCT handling.
Zhang et al. (Sun,) studied this question.